Pharmaceutical composition and preparation method therefor

ABSTRACT

The present invention provides an oral pharmaceutical composition and a usage thereof, comprising a pharmaceutically acceptable acidic medicinal auxiliary material whose surface is modified and dabigatran etexilate or pharmaceutically acceptable salts or aquo-complexes thereof. The present invention further provides a surface modification method for a medicinal auxiliary material.

TECHNICAL FIELD

The present invention relates to a pharmaceutical composition comprisinga pharmaceutically acceptable surface-modified acidic medicinalauxiliary material. In particular, the present invention relates to apharmaceutical composition comprising dabigatran etexilate (an activesubstance) or a pharmaceutically acceptable salt or hydrate thereof anda pharmaceutically acceptable surface-modified acidic medicinalauxiliary material. The present invention also relates to the field ofsurface modification of a medicinal auxiliary material, and inparticular, to a method for surface modification of a medicinalauxiliary material.

BACKGROUND ART

Many drugs will undergo a chemical reaction in the present of acidic oralkaline materials, resulting in a chemical degradation of the drugs. Ingeneral, the use of acidic or alkaline materials should be avoided inthe formulation products of drugs which decompose in the present ofacids or alkalis. However, in some special cases, some acidic oralkaline materials may be needed for such unstable drugs, so as toenable the formulation products of these drugs to meet certainrequirements.

Dabigatran etexilate is one of those drugs, which has the chemicalstructure of ethyl3-[(2-{4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionate,and the molecular formula of this compound is represented by thefollowing formula (I):

Dabigatran etexilate was developed by Germany Boehringer IngelheimCompany, and had first entered into market in Germany and the UK inApril 2008 and then was approved for marketing in American on Oct. 19,2010. The trade name in English of this drug is Pradaxa, and the generalname in English of this drug is dabigatran etexilate mesylate. Thegeneral name in Chinese of this drug is “

”.

This molecule is a binary prodrug. Esters are formed at both ends of themolecule. After entering into the body, the esters at both ends willundergo an enzymatic hydrolysis to form a dibasic acid, namelydabigatran, which is the exactly active pharmaceutical molecule.However, the structure of the dabigatran molecule is too polar topenetrate the intestinal wall cells, resulting in a very low oralbioavailability, and it can only penetrate the intestinal wall cells andbe orally administrated after it is esterified.

As a prodrug of dabigatran, dabigatran etexilate is a novel and the onlyoral type of direct thrombin inhibitor, and belongs to a nonpeptidicthrombin inhibitor. Upon gastrointestinal absorption after oraladministration, it is conversed in vivo to dabigatran having a directanticoagulant activity. By binding to fibrin-specific binding sites ofthrombin, dabigatran prevents the cleavage of fibrinogen into fibrin,thereby blocking the final step of the coagulation cascade network andthrombosis. Dabigatran can be dissociated from the fibrin-thrombincomplex and play a reversible anticoagulant effect. As compared with thetargets of other anticoagulants and platelet inhibitors in the priorart, the target of this drug is closer to the end of the reactioncascade, and thus this drug has a more definite mechanism of action anda better selectivity.

Dabigatran etexilate has a poor solubility, and in order to increase itssolubility, it is developed as a formulation and used clinically in theform of salt (dabigatran etexilate mesylate). The solubility ofdabigatran etexilate mesylate is strongly dependent on pH. Dabigatranetexilate mesylate has a high solubility in acidic media and a very poorsolubility in neutral and alkaline media and is substantially insolublein physiological conditions, namely, in the intestine near pH 7.0,resulting in a poor bioavailability.

Due to these physicochemical and biopharmaceutical properties ofdabigatran etexilate mesylate, some efforts have been made to obtain astable dabigatran etexilate mesylate composition exhibiting the desiredbioavailability.

Chinese Patent No. ZL03805473.6 discloses a formulation and processcharacterized by coating an insulating layer and an active substance(comprising dabigatran etexilate or a pharmaceutically acceptable saltthereof, preferably dabigatran etexilate mesylate) layer on asubstantially spherical acid core material which consists of or containsa pharmaceutically acceptable organic acid, wherein the organic acidcontained in the acid core material has a solubility of greater than 1g/250 ml in water at 20° C., and the organic acid core material and theactive substance layer are separated from each another by the insulatinglayer. The formulation (containing an organic acid) prepared by thisprocess has a significantly improved bioavailability as compared withconventional formulations (free of an organic acid), because the organicacid added into conventional formulations may produce in the aqueoussolution of the gastrointestinal tract an acid microenvironment (alsocalled as acid microclimate) in which dabigatran etexilate mesylate candissolve, enabling dabigatran etexilate mesylate to be absorbed in vivoafter being dissolved.

As mentioned in this patent, dabigatran etexilate mesylate is extremelyliable to acids, but it is necessary to add an organic acid to theformulation product in order to improve the bioavailability of theformulation product. In this patent, a high molecular weight polymer isused to coat the outer surface of pellets with a film so as to form aninsulating layer, and then the outer surface of the insulating layer iscoated with dabigatran etexilate mesylate. The process comprises loadingthe drug in a fluidized state onto the surface of the organic acid corematerial, that is, the drug is formulated into a suspension for loading.Accordingly, the process has the disadvantages of a low drug loadingrate, a great loss of drug, unevenness of drug loading, an uncertainamount of the drug loaded, complex operations and the like. Further, thespherical degree of the prepared organic acid pellet core, theperfection degree of the insulating layer coating, the combinationdegree of the active substance and the insulating layer etc. need to bestrictly controlled, resulting in high production costs and a longproduction period.

SUMMARY OF INVENTION

The present invention has been made in view of the above-mentionedproblems in the prior art, and an object of the present invention is toprovide an oral pharmaceutical composition of dabigatran etexilate or asalt or hydrate thereof, comprising a pharmaceutically acceptablesurface-modified acidic medicinal auxiliary material. The pharmaceuticalcomposition is chemically stable, exhibits a high solubility, andprovides the desired bioavailability. Meanwhile, the pharmaceuticalcomposition has a simple preparation process and low production costs,which solves many problems in the prior art process. Thepharmaceutically acceptable surface-modified acidic medicinal auxiliarymaterial of the present invention may be also applicable to otherpharmaceutical compositions which are labile to acids or alkalis in theformulation that however requires the use of acidic auxiliary materialsor alkaline auxiliary materials therein.

Specifically, the present invention provides a pharmaceuticallyacceptable surface-modified acidic medicinal auxiliary material oralkaline medicinal auxiliary material that is applicable topharmaceutical compositions which are labile to acids or alkalis in theformulation that however requires the use of acidic medicinal auxiliarymaterials or alkaline medicinal auxiliary materials therein.

More specifically, the present invention provides an oral pharmaceuticalcomposition comprising: a) a pharmaceutically acceptablesurface-modified acidic medicinal auxiliary material, b) ethyl3-[(2-{4-(hexyloxycarbonylamino-imino-methyl)-phenylamine]-methyl}-1-methyl-1H-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionatethat is also called as dabigatran etexilate, or a pharmaceuticallyacceptable salt or hydrate thereof.

Preferably, the pharmaceutically acceptable salt of dabigatran etexilateis dabigatran etexilate mesylate.

In an embodiment, the pharmaceutically acceptable surface-modifiedacidic medicinal auxiliary material or alkaline medicinal auxiliarymaterial is treated with an aqueous solution of an alkaline substancefor modification or an acidic substance for modification. Specifically,an aqueous solution of a pharmaceutically acceptable alkaline substancefor modification or a pharmaceutically acceptable acidic substance formodification is formulated, and powder particles of the acidic medicinalauxiliary material or the alkaline medicinal auxiliary material areadded to the aqueous solution of the alkaline substance for modificationor the acidic substance for modification, to form a neutral salt layeron the surface of the powder particles of the acidic medicinal auxiliarymaterial or the alkaline medicinal auxiliary material.

In an embodiment, the acidic medicinal auxiliary material is apharmaceutically acceptable water-soluble acidic solid. In a preferredembodiment, the acidic medicinal auxiliary material is apharmaceutically acceptable organic acid having a solubility of greaterthan 1% in water at 20° C. Further, the pH of 1% aqueous solutionformulated with the acidic medicinal auxiliary material should be lessthan or equal to 5. In a preferred embodiment, the acidic medicinalauxiliary material includes, but is not limited to, one ofpharmaceutically acceptable water-soluble organic acids such as tartaricacid, fumaric acid, succinic acid, citric acid, lactic acid and malicacid etc., or a hydrate or acidic salt thereof. In a preferredembodiment, the acidic medicinal auxiliary material also includes, butis not limited to, one of pharmaceutically acceptable water-solubleacidic amino acids such as glutamic acid and aspartic acid etc., or ahydrate or acidic salt thereof, or acidic salts of otherpharmaceutically acceptable water-soluble amino acids such as acidicsalts of glycine, alanine and serine etc. In a preferred embodiment, theacidic medicinal auxiliary material also includes, but is not limitedto, one of acidic salts of pharmaceutically acceptable water-solubleinorganic acids such as dihydrogenphosphates and bisulfates etc., or ahydrate thereof.

In an embodiment, the alkaline medicinal auxiliary material is apharmaceutically acceptable water-soluble alkaline solid. In a preferredembodiment, the alkaline medicinal auxiliary material is apharmaceutically acceptable alkaline substance having a solubility ofgreater than 1% in water at 20° C. Further, the pH of 1% aqueoussolution formulated with the alkaline medicinal auxiliary materialshould be greater than or equal to 9. In a preferred embodiment, thealkaline medicinal auxiliary material includes, but is not limited to,one of pharmaceutically acceptable water-soluble organic alkalis such asmeglumine and trihydroxymethylaminomethane etc., or a hydrate thereof.In a preferred embodiment, the alkaline medicinal auxiliary materialincludes, but is not limited to, one of pharmaceutically acceptablewater-soluble alkaline amino acids such as lysine, arginine, andhistidine etc., or a hydrate or alkaline salt thereof, or alkaline saltsof other pharmaceutically acceptable water-soluble amino acids such asalkaline salts of glycine, alanine and serine etc. In a preferredembodiment, the alkaline medicinal auxiliary material includes, but isnot limited to, one of alkaline salts of pharmaceutically acceptablewater-soluble inorganic acids such as alkaline carbonates and alkalinephosphates etc., or a hydrate thereof.

In an embodiment, the alkaline substance for modification is apharmaceutically acceptable water-soluble alkaline solid or liquid. In apreferred embodiment, the alkaline substance for modification is apharmaceutically acceptable alkaline substance having a solubility ofgreater than 1% in water at 20° C. Further, the pH of 1% aqueoussolution formulated with the alkaline substance for modification shouldbe greater than or equal to 9. In a preferred embodiment, the alkalinesubstance for modification includes, but is not limited to, one ofpharmaceutically acceptable water-soluble inorganic alkaline substancessuch as hydroxide salts, water-soluble alkaline carbonates andwater-soluble alkaline phosphates etc., or a hydrate thereof. In apreferred embodiment, the alkaline substance for modification includes,but is not limited to, one of pharmaceutically acceptable water-solubleorganic alkaline substances such as aqueous ammonia, meglumine andtrihydroxymethylaminomethane etc., or a hydrate thereof. In a preferredembodiment, the alkaline substance for modification includes, but is notlimited to, one of alkaline salts of pharmaceutically acceptablewater-soluble organic weak acids such as alkaline salts of acetic acid,tartaric acid, fumaric acid, succinic acid, citric acid, malic acid andlactic acid etc., or a hydrate thereof. In a preferred embodiment, thealkaline substance for modification includes, but is not limited to, oneof some pharmaceutically acceptable alkaline amino acids such as lysine,arginine, and histidine etc., or a hydrate or alkaline salt thereof, oralkaline salts of other water-soluble amino acids such as alkaline saltsof glycine, alanine and serine etc.

In an embodiment, the acidic substance for modification is apharmaceutically acceptable water-soluble acidic solid or liquid. In apreferred embodiment, the acidic substance for modification is apharmaceutically acceptable acidic substance having a solubility ofgreater than 1% in water at 20° C. Further, the pH of 1% aqueoussolution formulated with the acidic substance for modification should beless than or equal to 5. In a preferred embodiment, the acidic substancefor modification includes, but is not limited to, one ofpharmaceutically acceptable water-soluble organic acids such as tartaricacid, fumaric acid, succinic acid, citric acid and malic acid etc., or ahydrate thereof. In a preferred embodiment, the acidic substance formodification includes, but is not limited to, one of pharmaceuticallyacceptable acidic amino acids such as glutamic acid and aspartic acid,or a hydrate or acidic salt thereof, or acidic salts of otherwater-soluble amino acids such as acidic salts of glycine, alanine andserine etc. In a preferred embodiment, the acidic substance formodification includes, but is not limited to, one of pharmaceuticallyacceptable water-soluble inorganic acids or acidic salts thereof such ashydrochloric acid, sulfuric acid, bisulfates, phosphoric acid,dihydrogenphosphates and bromic acid etc., or a hydrate thereof. In apreferred embodiment, the acidic substance for modification includes,but is not limited to, one of acidic salts of pharmaceuticallyacceptable water-soluble organic alkalis such as acidic salts ofmeglumine and trihydroxymethylaminomethane etc., or a hydrate thereof.

In an embodiment, the aqueous solution of the alkaline substance formodification or the acidic substance for modification has aconcentration in the range of 1 wt % to a saturation concentration,preferably 5 to 40 wt %, more preferably 20 wt %. The saturationconcentration of the aqueous solution of the alkaline substance formodification or the acidic substance for modification depends on thewater solubility of the alkaline substance or acidic substance forsurface modification.

In an embodiment, the powder particles of the acidic medicinal auxiliarymaterial or the alkaline medicinal auxiliary material have a particlesize of 0.4 to 1.5 mm, and pass through a 40 mesh to 60 mesh sieve.

In an embodiment, the pharmaceutical composition is loaded intohydroxypropylmethylcellulose capsules.

In an embodiment, the weight ratio of the added alkaline or acidicsubstance for modification to the acidic or alkaline medicinal auxiliarymaterial solid to be modified is 0.1% to 10%, and the solid ratio ispreferably 0.67% to 4%, more preferably 2%.

Pharmaceutically acceptable excipients which may be incorporated intothe composition of the present invention include, but are not limitedto, binders, disintegrants, diluents, surfactants, glidants, lubricants,etc., or combinations thereof.

Binders, disintegrants, diluents, surfactants, glidants, lubricants,etc., are exemplified below. It is necessary to disclose somepharmaceutically acceptable excipients herein, because some of theexcipients are disclosed in the following examples.

The term “pharmaceutically acceptable salt” as used in the presentinvention refers to those salts which are suitable for use in contactwith tissues of humans and other mammals without excessive toxicity,irritation, allergic reactions, etc., according to medical criteria.Such pharmaceutically acceptable salts are well known in the art.

In another aspect, the present invention also provides a process forpreparing a pharmaceutical composition containing dabigatran etexilateor a pharmaceutically acceptable salt or hydrate thereof, comprising thestep of mixing a pharmaceutically acceptable surface-modified acidicmedicinal auxiliary material with dabigatran etexilate or apharmaceutically acceptable salt or hydrate thereof, and optionally, atleast one pharmaceutically acceptable excipients. Further, thepharmaceutically acceptable surface-modified acidic medicinal auxiliarymaterial is prepared by the following process: according to the watersolubility of the alkaline substance for modification, formulating anaqueous solution of the pharmaceutically acceptable alkaline substancefor modification at a concentration of 1 wt % to the saturationconcentration (preferably 5 to 40 wt %, more preferably 20 wt %); addingthe acidic medicinal auxiliary material having a particle size of 0.4 to1.5 mm, preferably 0.5 mm, to a certain volume of the above formulatedaqueous solution of the pharmaceutically acceptable alkaline substancefor modification; alkalizing the surface of powder particles of theacidic medicinal auxiliary material with the aqueous solution of thealkaline substance for modification, to form a neutral salt layer on thesurface of the powder particles of the acidic medicinal auxiliarymaterial. The acidic medicinal auxiliary material is a pharmaceuticallyacceptable organic acid having a solubility of greater than 1% in waterat 20° C., and the organic acid as the acidic medicinal auxiliarymaterial is one selected from the group consisting of tartaric acid,fumaric acid, succinic acid, citric acid, malic acid, glutamic acid andaspartic acid, or a hydrate or acidic salt thereof, preferably tartaricacid. The pharmaceutically acceptable alkaline substance formodification as used for alkalization is a pharmaceutically acceptablealkaline substance for modification, and the pharmaceutically acceptablealkaline substance for modification is one of sodium carbonate,potassium carbonate, sodium acetate, potassium acetate, sodium stearate,potassium stearate, lysine, arginine and histidine, or a hydratethereof, preferably sodium carbonate. In addition to sodium carbonate,any weak-acid strong-alkali salts which are alkaline in an aqueoussolution can be used in the present invention, without any particularlimitation.

Specifically, the pharmaceutically acceptable surface-modified acidicmedicinal auxiliary material may be prepared by the following process:first, formulating a sodium carbonate aqueous solution at aconcentration of about 20% (by weight); with stirring, adding 10% of theabove formulated sodium carbonate aqueous solution having aconcentration of about 20% to tartaric acid powder particles having aparticle size of 40 to 60 mesh; and after stirring, drying the tartaricacid powder particles in a drying apparatus such as a drying oven or afluidized bed, to yield the modified tartaric acid powder particles.

The present invention has been made in view of the above-mentionedproblems in the prior art, and an object of the present invention is toprovide a method for surface modification of a medicinal auxiliarymaterial, which has a simple process, achieves low production costs, andis applicable to the preparation of drugs which are liable to acids oralkalis in the formulation that however requires the use of acidicauxiliary materials or alkaline auxiliary materials therein.

To achieve the above object, the method for surface modification of amedicinal auxiliary material according to the present invention ischaracterized in that it comprises formulating an aqueous solution of apharmaceutically acceptable alkaline substance for modification or apharmaceutically acceptable acidic substance for modification; addingpowder particles of an acidic medicinal auxiliary material or analkaline medicinal auxiliary material to the aqueous solution of thealkaline substance for modification or the acidic substance formodification, to form a neutral salt layer on the surface of the powderparticles of the acidic medicinal auxiliary material or the alkalinemedicinal auxiliary material, wherein the acidic medicinal auxiliarymaterial is a pharmaceutically acceptable organic acid having a watersolubility of greater than 1 g/250 mL at 20° C., and the alkalinemedicinal auxiliary material is a pharmaceutically acceptable alkalinesubstance having a water solubility of greater than 1 g/250 mL at 20° C.

Further, the pharmaceutically acceptable organic acid as the acidicmedicinal auxiliary material is one of tartaric acid, fumaric acid,succinic acid, citric acid, malic acid, glutamic acid and aspartic acid,or a hydrate or acidic salt thereof.

Further, the pharmaceutically acceptable alkaline substance as thealkaline medicinal auxiliary material is one of lysine, arginine andhistidine, or a hydrate thereof.

Further, the pharmaceutically acceptable alkaline substance formodification is one of sodium carbonate, potassium carbonate, sodiumacetate, potassium acetate, sodium stearate, potassium stearate, lysine,arginine and histidine, or a hydrate thereof.

Further, the pharmaceutically acceptable acidic substance formodification is one of tartaric acid, fumaric acid, succinic acid,citric acid, malic acid, glutamic acid and aspartic acid, or a hydrateor acidic salt thereof, or one of sodium bisulfate, sodiumdihydrogenphosphate and stearic acid, or a hydrate thereof.

Further, the aqueous solution of the alkaline substance for modificationor the acidic substance for modification has a concentration of 5 to 40wt %, and the concentration of the aqueous solution of the alkalinesubstance for modification or the acidic substance for modificationdepends on the water solubility of the alkaline substance or acidicsubstance for surface modification.

Further, the powder particles of the acidic medicinal auxiliary materialor the alkaline medicinal auxiliary material have a particle size of 0.4to 1.5 mm.

As described above, by chemically forming a neutral salt layer on thesurface of the acidic medicinal auxiliary material or the alkalinemedicinal auxiliary material, the pharmaceutical composition of thepresent invention separates the acidic medicinal auxiliary material orthe alkaline medicinal auxiliary material from the active drugingredient which is labile to acids or alkalis in the formulation thathowever requires the use of acidic auxiliary materials or alkalineauxiliary materials therein, thereby improving the storage stability ofthe drug. Furthermore, this method utilizes only an one-step reaction tomodify the surface of the acidic medicinal auxiliary material or thealkaline medicinal auxiliary material, and thus has simple operationsand achieves low production costs. The method for surface modificationof a medicinal auxiliary material according to the present inventionperforms the modification of the surface of the acidic medicinalauxiliary material or the alkaline medicinal auxiliary material by onlyan one-step reaction, and thus has a simple process and achieves lowproduction costs.

By chemically forming a neutral salt layer on the surface of the acidicmedicinal auxiliary material or the alkaline medicinal auxiliarymaterial, the present invention separates the acidic medicinal auxiliarymaterial or the alkaline medicinal auxiliary material from the activedrug ingredient which is labile to acids or alkalis in the formulationthat however requires the use of acidic medicinal auxiliary materials oralkaline medicinal auxiliary materials therein, thereby improving thestorage stability of the drug.

The pharmaceutical composition containing dabigatran etexilate preparedas described above is useful for the following clinical indications: 1)for preventing deep venous thrombosis and pulmonary embolism afterartificial (knee or hip) arthroplasty, in which case an anticoagulantdrug is conventionally used after the surgery; 2) for preventing strokeand thrombosis in a patient with abnormal heart rhythm (atrialfibrillation).

DESCRIPTION OF DRAWINGS

FIG. 1 shows that the drug obtained in Example 2 achieves the samedissolution effect as the prior art product.

FIG. 2 shows the dissolution results of the capsules of Example 3 whichwere prepared with the raw material dabigatran etexilate mesylate andthe modified tartaric acid in different proportions.

DESCRIPTION OF EMBODIMENTS

To clearly illustrate the object, the technical solution and theadvantages of the present invention, the specific embodiments of thepresent invention will be described below in detail, with reference tothe accompanying drawings.

The technical solutions in the examples of the present invention will bedescribed below in detail, with reference to the examples of the presentinvention. Obviously, the examples described herein are merely a part ofthe examples of the present invention, and do not represent all. On thebasis of the examples shown in the present invention, all the otherexamples which can be obtained by those of ordinary skill in the artwithout paying any creative efforts are within the scope of the presentinvention.

It should be noted that in this context, the terms “comprise”,“include”, and “contain” or any other variants thereof are intended tobe nonexclusive, so that a process, method, article or apparatuscomprising a series of elements includes not only those elements, butalso other elements which are not explicitly listed, or elements whichare inherent to such a process, method, article, or apparatus.Meanwhile, in the present invention, the dissolution is tested at 100rpm and at a temperature of 37° C. by the basket method specified in thePharmacopoeia, and water is used as the solvent.

FIG. 1 shows that the drug obtained according to Formula 2 achieves thesame dissolution effect as the prior art product. FIG. 2 shows thedissolution results of the capsules prepared with the raw materialdabigatran etexilate mesylate and the modified tartaric acid indifferent proportions.

The method for surface modification of an acidic medicinal auxiliarymaterial according to the present invention comprises: according to thewater solubility of the alkaline substance for modification, formulatingan aqueous solution of the pharmaceutically acceptable alkalinesubstance for modification at a concentration of 5 to 40 wt %; addingthe acidic medicinal auxiliary material having a particle size of 0.4 to1.5 mm, preferably 0.5 mm, to a certain volume of the above formulatedaqueous solution of the pharmaceutically acceptable alkaline substancefor modification having a concentration of 5 to 40 wt %; alkalizing thesurface of powder particles of the acidic medicinal auxiliary materialwith the above aqueous solution of the alkaline substance formodification, to form a neutral salt layer on the surface of the powderparticles of the acidic medicinal auxiliary material. The acidicmedicinal auxiliary material is a pharmaceutically acceptable organicacid having a water solubility of greater than 1 g/250 mL at 20° C., andthe organic acid as the acidic medicinal auxiliary material is oneselected from the group consisting of tartaric acid, fumaric acid,succinic acid, citric acid, malic acid, glutamic acid and aspartic acid,or a hydrate or acidic salt thereof, preferably tartaric acid. Thepharmaceutically acceptable alkaline substance for modification as usedfor alkalization is a pharmaceutically acceptable alkaline substance formodification, and the pharmaceutically acceptable alkaline substance formodification is one of sodium carbonate, potassium carbonate, sodiumacetate, potassium acetate, sodium stearate, potassium stearate, lysine,arginine and histidine, or a hydrate thereof, preferably sodiumcarbonate.

First, a sodium carbonate aqueous solution having a concentration of 20%(by weight) is formulated; with stirring, 10% of the above formulatedsodium carbonate aqueous solution having a formulation concentration of20% is added to tartaric acid powder particles having a particle size of0.4 to 1.5 mm, preferably 0.5 mm; and after stirring, the tartaric acidpowder particles are dried in a drying apparatus such as a drying ovenor a fluidized bed, to yield the modified tartaric acid powderparticles.

Since the sodium carbonate aqueous solution is alkaline, a chemicalreaction will occur between the alkaline sodium carbonate and the acidictartaric acid, forming a neutral salt layer on the surface of thetartaric acid powder particles. The neutral salt layer separates theacidic medicinal auxiliary material tartaric acid from the active drugingredient which is labile to acids in the formulation that howeverrequires the use of acidic auxiliary materials therein, therebyimproving the storage stability of the drug. In addition to sodiumcarbonate, any weak-acid strong-alkali salts which are alkaline in anaqueous solution can be used in the present invention, without anyparticular limitation.

Example 1 Formula 1

Dabigatran etexilate mesylate 173.0 mg Tartaric acid 173.5 mg Sodiumcarbonate 3.54 mg Total 350 mg Control formula: Dabigatran etexilatemesylate 173.0 mg Tartaric acid 177 mg Total 350 mg

Dabigatran etexilate mesylate, tartaric acid, and sodium carbonate areall commercially available raw materials.

According to Formula 1, a quantified amount of sodium carbonate wasdissolved in 20 mL water; with stirring, tartaric acid powder particleshaving a particle size of 0.4 to 1.5 mm were added to the sodiumcarbonate aqueous solution; and after stirring, the tartaric acid powderparticles were dried in a drying apparatus such as a drying oven or afluidized bed, to yield the modified tartaric acid powder particles.

The modified tartaric acid powder particles were thoroughly mixed withdabigatran etexilate mesylate indicated in Formula 1 and loaded intohydroxypropylmethylcellulose (HPMC) capsules. The capsules were thenpacked into high density polyethylene (HDPE) bottles containing adesiccant. After being stored at 75° C. and 75% RH for 1 week and 2weeks, capsule samples were tested by HPLC and the results are shown inthe following table.

According to the control formula, tartaric acid powder particles werethoroughly mixed with dabigatran etexilate mesylate indicated in thecontrol formula and loaded into hydroxypropylmethylcellulose (HPMC)capsules. The capsules were then packed into high density polyethylene(HDPE) bottles containing a desiccant. After being stored at 75° C. and75% RH for 1 week and 2 weeks, capsule samples were tested by HPLC andthe results are shown in the following table.

TABLE 1 Total amount of decomposition products (%) Storage durationFormula 1 Control formula 0 day 0.27 0.31 1 week 2.9 3.6 2 weeks 4.810.9

As can be seen from the above results, the formulation into which themodified tartaric acid was added exhibits a greatly improved storagestability. As shown in Table 1, it can be seen that as the storageduration changes, the stability is 200% or more relative to theunmodified control.

Example 2 Formula 2

Dabigatran etexilate mesylate 173.0 mg Tartaric acid 166.6 mg Sodiumcarbonate 3.4 mg HPC 10.0 mg Silica powder 8.0 mg SDS 5.0 mg Lactose45.0 mg Magnesium stearate 6.0 mg Total 420.0 mg

According to Formula 2, a quantified amount of sodium carbonate wasdissolved in 20 mL water; with stirring, tartaric acid powder particleshaving a particle size of 0.4 to 1.5 mm were added to the sodiumcarbonate aqueous solution; and after stirring, the tartaric acid powderparticles were dried in a drying apparatus such as a drying oven or afluidized bed, to yield the modified tartaric acid powder particles.

Then, dabigatran etexilate mesylate were mixed with the modifiedtartaric acid powder particles, followed by other pharmaceuticallyacceptable excipients, and loaded into HPMC capsules to yield thepharmaceutical formulation product.

Example 3

Dabigatran etexilate mesylate were mixed with the modified tartaric acidpowder particles, followed by other pharmaceutically acceptableexcipients, and loaded into HPMC capsules to yield the pharmaceuticalformulation product. FIG. 2 shows the dissolution results of thecapsules prepared with the raw material dabigatran etexilate mesylateand the modified tartaric acid in different proportions. The dissolutionwas tested at 100 rpm and at a temperature of 37° C. by the basketmethod specified in the Pharmacopoeia, and water was used as thesolvent.

The results show that the dissolution of the dabigatran etexilatemesylate formulation product into which the modified tartaric acid wasadded is significantly improved as compared with the dissolution of theformulation into which the modified tartaric acid was not added.

To sum up, the pharmaceutical composition of the present inventionexhibits a superior storage stability, achieves a high solubility, andprovides the desired bioavailability. Meanwhile, the method for surfacemodification of a medicinal auxiliary material performs the modificationof the surface of the acidic medicinal auxiliary material by only anone-step reaction, and thus has a simple process and achieves lowproduction costs.

The specific embodiments described above are merely illustrative of thespirit of the present invention, and the scope of the present inventionis not limited thereto. It will be apparent to those skilled in the artthat, other embodiments can be readily made by way of modifications,replacements or variations according to the technical contents disclosedin the present Description, and all of the other embodiments areintended to be within the scope of the present invention.

What is claimed is:
 1. A method of producing a pharmaceuticalcomposition comprising an active pharmaceutical ingredient or apharmaceutically acceptable salt or hydrate thereof, and apharmaceutically acceptable surface-modified acidic auxiliary material,the method comprising: (a) formulating an aqueous solution of apharmaceutically acceptable alkaline substance for modification; (b)contacting powder particles of an acidic medicinal auxiliary materialwith the aqueous solution of the pharmaceutically acceptable alkalinesubstance for modification, wherein said powder particles comprise asurface; (c) forming a neutral salt layer on the surface of the powderparticles of the acidic medicinal auxiliary material to produce thepharmaceutically acceptable surface-modified acidic auxiliary material;and (d) contacting the active pharmaceutical ingredient or apharmaceutically acceptable salt or hydrate thereof with thepharmaceutically acceptable surface-modified acidic auxiliary material,wherein the acidic medicinal auxiliary material is selected from thegroup consisting of tartaric acid, fumaric acid, succinic acid, citricacid, malic acid, glutamic acid, aspartic acid, a hydrate thereof, andan acidic salt thereof, and wherein the pharmaceutically acceptablealkaline substance for modification is selected from the groupconsisting of aqueous ammonia, meglumine, trihydroxymethylaminomethane,sodium carbonate, potassium carbonate, sodium acetate, potassiumacetate, sodium stearate, potassium stearate, lysine, arginine,histidine, and a hydrate thereof.
 2. The method of claim 1, wherein aweight ratio of the pharmaceutically acceptable alkaline substance formodification to the acidic medicinal auxiliary material in thepharmaceutical composition is up to 10%.
 3. The method of claim 1,wherein a weight ratio of the pharmaceutically acceptable alkalinesubstance for modification to the acidic medicinal auxiliary material inthe pharmaceutical composition is 0.1% to 10%.
 4. The method of claim 1,wherein a weight ratio of the pharmaceutically acceptable alkalinesubstance for modification to the acidic medicinal auxiliary material inthe pharmaceutical composition is 0.67% to 4%.
 5. The method of claim 1,wherein the pharmaceutically acceptable alkaline substance formodification is selected from the group consisting of sodium carbonate,potassium carbonate, sodium acetate, potassium acetate, lysine, arginineand a hydrate thereof.
 6. The method of claim 1, wherein thepharmaceutically acceptable alkaline substance for modification issodium carbonate.
 7. The method of claim 1, wherein the aqueous solutionof the pharmaceutically acceptable alkaline substance for modificationhas a concentration of 5 to 40 wt %.
 8. The method of claim 1, whereinthe acidic medicinal auxiliary material is tartaric acid.
 9. The methodof claim 1, wherein the acidic salt is selected from the groupconsisting of sodium bisulfate, sodium dihydrogenphosphate, stearicacid, and a hydrate thereof.
 10. The method of claim 1, wherein theacidic medicinal auxiliary material has a particle size of 0.4 to 1.5mm.
 11. The method of claim 1, wherein the acidic medicinal auxiliarymaterial has a particle size that passes through a 40 mesh to 60 meshsieve.
 12. The method of claim 1, wherein the acidic medicinal auxiliarymaterial is present in the pharmaceutical composition in an amount of40% to 50% by weight.
 13. The method of claim 1, further comprisingdrying the pharmaceutically acceptable surface-modified acidic auxiliarymaterial.
 14. The method of claim 1, further comprising mixing theactive pharmaceutical ingredient or a pharmaceutically acceptable saltor hydrate thereof with the pharmaceutically acceptable surface-modifiedacidic auxiliary material.
 15. The method of claim 1, further comprisingloading the active pharmaceutical ingredient or a pharmaceuticallyacceptable salt or hydrate thereof and the pharmaceutically acceptablesurface-modified acidic auxiliary material intohydroxypropylmethylcellose (HPMC) capsules.
 16. A method of producing apharmaceutical composition comprising an active pharmaceuticalingredient or a pharmaceutically acceptable salt or hydrate thereof, anda pharmaceutically acceptable surface-modified alkaline auxiliarymaterial, the method comprising: (a) formulating an aqueous solution ofa pharmaceutically acceptable acidic substance for modification; (b)contacting powder particles of an alkaline medicinal auxiliary materialwith the aqueous solution of the pharmaceutically acceptable acidicsubstance for modification, wherein said powder particles comprise asurface; (c) forming a neutral salt layer on the surface of the powderparticles of the alkaline medicinal auxiliary material to produce thepharmaceutically acceptable surface-modified alkaline auxiliarymaterial; and (d) contacting the active pharmaceutical ingredient or apharmaceutically acceptable salt or hydrate thereof with thepharmaceutically acceptable surface-modified alkaline auxiliarymaterial, wherein the alkaline medicinal auxiliary material is selectedfrom the group consisting of lysine, arginine, histidine, and a hydratethereof, and wherein the pharmaceutically acceptable acidic substancefor modification is selected from the group consisting of tartaric acid,fumaric acid, succinic acid, citric acid, malic acid, glutamic acid,aspartic acid, a hydrate thereof, and an acidic salt.